Severe vitamin B12 deficiency has been produced in Rhesus monkeys by feeding a defined experimental diet under controlled conditions. Four years after initiating our study no significant deviations from the normal exist in the morphology or counts of either peripheral blood or bone marrow. Methylmalonic acid excretion has been abnormal only in the deficient animals. In 5 of the deficient animals gross visual impairment has recently become evident, confirmed ophthalmoscopically by optic atrophy in 2 and temporal pallor in 3. Histopathologic examination of 3 deficient animals disclosed degeneration of the papillomacular bundle in the optic nerves, extensive demyelination and axon loss within the optic chiasm and tracts, and transynaptic degeneration of the lateral geniculate bodies. No changes were demonstrated in the spinal cord, peripheral nerves or centrum ovale. No pathologic changes were found in one hydroxycobalamin-supplemented animal. Three of the 5 surviving animals now show weakness of their hind limbs with spasticity and brisk reflexes. It is proposed to continue these studies (1) pursuing to completion the observations already begun (light and electron microscopy, total lipid analysis and study of the propionate and acetate pathways by radioisotopic techniques in the nervous system, peripheral blood and viscera); (2) expanding these observations to animals now sharing hind limb spasticity and weakness as well as to 4 new animals per year to be added to the experiment; and (3) examining the correlation or lack of correlation between clinical, histological and ultrastructural abnormalities and the various biochemical and enzymatic alterations that have been described for B12 deficiency.